Enzymatic control of cycloadduct conformation ensures reversible 1,3-dipolar cycloaddition in a prFMN-dependent decarboxylase

The UbiD enzyme plays an important role in bacterial ubiquinone (coenzyme Q) biosynthesis. It belongs to a family of reversible decarboxylases that interconvert propenoic or aromatic acids with the corresponding alkenes or aromatic compounds using a prenylated flavin mononucleotide cofactor. This co...

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Bibliographic Details
Published in:Nature chemistry 2019-11, Vol.11 (11), p.1049-1057
Main Authors: Bailey, Samuel S, Payne, Karl A P, Saaret, Annica, Marshall, Stephen A, Gostimskaya, Irina, Kosov, Iaroslav, Fisher, Karl, Hay, Sam, Leys, David
Format: Article
Language:English
Subjects:
Acids
Alkenes
Alkynes - chemistry
Alkynes - metabolism
Aromatic compounds
Biocatalysis
Biosynthesis
Carboxy-Lyases - chemistry
Carboxy-Lyases - isolation & purification
Carboxy-Lyases - metabolism
Carboxylation
Catalysis
Cinnamic acid
Coenzyme Q
Computer applications
Conformation
Cycloaddition
Cycloaddition Reaction
Density Functional Theory
Enzymes
Ferulic acid
Flavin mononucleotide
Intermediates
Models, Molecular
Molecular Conformation
Mutagenesis
Propionates - chemistry
Propionates - metabolism
Ubiquinone
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Summary:The UbiD enzyme plays an important role in bacterial ubiquinone (coenzyme Q) biosynthesis. It belongs to a family of reversible decarboxylases that interconvert propenoic or aromatic acids with the corresponding alkenes or aromatic compounds using a prenylated flavin mononucleotide cofactor. This cofactor is suggested to support (de)carboxylation through a reversible 1,3-dipolar cycloaddition process. Here, we report an atomic-level description of the reaction of the UbiD-related ferulic acid decarboxylase with substituted propenoic and propiolic acids (data ranging from 1.01-1.39 Å). The enzyme is only able to couple (de)carboxylation of cinnamic acid-type compounds to reversible 1,3-dipolar cycloaddition, while the formation of dead-end prenylated flavin mononucleotide cycloadducts occurs with distinct propenoic and propiolic acids. The active site imposes considerable strain on covalent intermediates formed with cinnamic and phenylpropiolic acids. Strain reduction through mutagenesis negatively affects catalytic rates with cinnamic acid, indicating a direct link between enzyme-induced strain and catalysis that is supported by computational studies.
ISSN:1755-4330
1755-4349
DOI:10.1038/s41557-019-0324-8